Pyruvate kinase deficiency anaemia is a rare genetic blood disorder that causes red blood cells to break down too quickly, leading to chronic anaemia and a range of symptoms that vary greatly from person to person. Understanding how this condition is managed—from traditional supportive care to emerging therapies being tested in clinical trials—can help patients and families navigate the challenges of living with this lifelong disorder.

How Treatment Approaches Support People with Pyruvate Kinase Deficiency

The main goal when treating pyruvate kinase deficiency is to manage the symptoms that arise when red blood cells break down faster than the body can replace them. This process, known as haemolytic anaemia, means the body struggles to deliver enough oxygen to tissues and organs. Treatment focuses on reducing the impact of anaemia, preventing complications like gallstones or iron overload, and improving the overall quality of life for patients.^[1]

Because pyruvate kinase deficiency affects people differently, treatment plans must be tailored to each individual. Some patients may have severe anaemia from birth and require frequent medical interventions, while others may experience only mild symptoms that worsen during illness, pregnancy, or other times of physical stress. The severity of symptoms does not always match the level of anaemia seen in blood tests, because the body sometimes compensates by increasing a substance called 2,3-diphosphoglycerate in red blood cells, which helps release oxygen more efficiently to tissues.^[7]

Standard treatments approved by medical societies focus on supportive care, meaning they help manage symptoms rather than correcting the underlying enzyme deficiency. However, research into new therapies is ongoing, with clinical trials testing drugs designed to address the root cause of the disease by boosting the activity of the faulty pyruvate kinase enzyme. These developments offer hope for more effective, disease-modifying treatments in the future.^[10]

Standard Treatment Options for Managing Symptoms

For many years, the cornerstone of managing pyruvate kinase deficiency has been supportive care. This means doctors focus on treating the consequences of haemolytic anaemia rather than the enzyme defect itself. The specific treatments used depend on the severity of the condition and the complications that arise in each patient.^[13]

Blood transfusions are one of the most common interventions, particularly for patients with severe anaemia or those experiencing sudden worsening of their condition, known as an aplastic crisis. During a transfusion, healthy red blood cells from a donor are given to the patient through an intravenous line. The decision to transfuse is not based solely on haemoglobin levels, but on how well the patient tolerates their anaemia and whether they are experiencing symptoms like extreme fatigue, shortness of breath, or rapid heartbeat.^[11]

Newborns and young children with pyruvate kinase deficiency often require transfusions more frequently than older children or adults. Studies show that about 53% of children under five years of age need regular transfusions, compared to around 31% of those aged five to twelve. As children grow, many are able to tolerate lower haemoglobin levels and require fewer transfusions. Some patients never need transfusions at all, while others depend on them throughout their lives.^[11]

When a patient receives repeated blood transfusions, iron can accumulate in the body because each unit of blood contains iron. Over time, this iron overload can damage vital organs like the heart and liver. To prevent this, doctors prescribe iron chelation therapy, which involves medications that bind to excess iron and help the body eliminate it. Regular monitoring of iron levels is essential for patients who receive frequent transfusions.^[12]

Folic acid supplementation is another standard part of care. Folic acid is a B vitamin that plays a crucial role in making new red blood cells. Because patients with pyruvate kinase deficiency are constantly producing red blood cells at a higher rate to compensate for those that break down, their bodies use up folic acid more quickly than normal. Taking a daily folic acid supplement helps prevent deficiency and supports healthy red blood cell production.^[11]

Phototherapy is commonly used in newborns with pyruvate kinase deficiency who develop severe jaundice. Jaundice occurs when a substance called bilirubin, released from broken-down red blood cells, builds up in the blood and causes yellowing of the skin and eyes. Phototherapy uses special blue light to help break down bilirubin so the body can eliminate it more easily. In severe cases, newborns may require exchange transfusions, where a large portion of the baby’s blood is replaced with donor blood to rapidly reduce bilirubin levels. Registry data shows that 93% of newborns with pyruvate kinase deficiency are treated with phototherapy, and 46% require exchange transfusions.^[11]

Splenectomy, or surgical removal of the spleen, is considered for patients who require frequent transfusions or have significant symptoms despite other treatments. The spleen is an organ that filters blood and removes old or damaged red blood cells. In pyruvate kinase deficiency, the spleen works overtime removing abnormal red blood cells, which worsens anaemia. Removing the spleen can reduce the rate at which red blood cells are destroyed and improve haemoglobin levels.^[13]

An international registry found that splenectomy was performed in 59% of patients with pyruvate kinase deficiency. After the procedure, patients experienced a median increase in haemoglobin of 1.6 grams per decilitre, and 90% of patients who had been receiving transfusions needed them less often or not at all. However, splenectomy is not a cure. Red blood cells continue to be removed in the liver, so the procedure only partially improves the anaemia. Doctors try to delay splenectomy in children until they are at least five years old, because the spleen plays an important role in fighting infections, especially in young children.^[11]

After splenectomy, patients face a lifelong increased risk of serious bacterial infections, particularly from organisms like pneumococcus, meningococcus, and haemophilus. To reduce this risk, patients receive vaccinations before surgery and may need to take preventive antibiotics. They should also be educated about recognizing signs of infection and seeking prompt medical care if they develop a fever or feel unwell.^[19]

Many patients who undergo splenectomy also develop gallstones over time. These small, pebble-like deposits form in the gallbladder from the buildup of bilirubin. In the registry study, 34% of patients had both splenectomy and gallbladder removal (cholecystectomy). Among those who had splenectomy without gallbladder removal, 48% later required surgery to remove their gallbladder. For this reason, some surgeons perform both procedures at the same time.^[11]

Emerging Therapies Being Tested in Clinical Trials

For decades, there were no medications specifically designed to treat the underlying enzyme deficiency in pyruvate kinase deficiency. All treatments focused on managing symptoms. This changed in February 2022, when the United States Food and Drug Administration (FDA) approved mitapivat (brand name Pyrukynd), the first drug designed to directly address the enzyme problem in pyruvate kinase deficiency.^[11]

Mitapivat belongs to a new class of drugs called pyruvate kinase activators. It works by binding to the pyruvate kinase enzyme in red blood cells and increasing its activity. This helps red blood cells produce more ATP, the energy molecule they need to survive. By boosting enzyme function, mitapivat addresses the root cause of the disease rather than just treating its symptoms.^[17]

The drug is taken orally, usually twice a day, which makes it more convenient than treatments requiring hospital visits for transfusions or procedures. Mitapivat has been shown to work with both normal pyruvate kinase enzymes and the mutant versions caused by genetic mutations in the PKLR gene. This is important because most patients with pyruvate kinase deficiency carry two different faulty copies of the gene (compound heterozygotes), each producing a different mutant enzyme.^[17]

Clinical trials of mitapivat included patients with varying degrees of disease severity. In these studies, patients who took mitapivat showed improvements in haemoglobin levels, meaning they had more red blood cells circulating in their blood. They also experienced improvements in markers of haemolysis, such as reductions in bilirubin and reticulocytes (immature red blood cells that the body produces at high rates to compensate for red blood cell loss). Many patients reported feeling less fatigued and having more energy to carry out daily activities.^[17]

Perhaps most importantly, patients who were dependent on regular blood transfusions before starting mitapivat often needed fewer transfusions or were able to stop transfusions altogether. This reduces the burden of frequent hospital visits and lowers the risk of complications like iron overload. For patients who were not transfusion-dependent, mitapivat helped maintain stable haemoglobin levels and improved their quality of life.^[17]

However, mitapivat does not work for everyone. The effectiveness of the drug depends in part on the type of genetic mutation a patient carries. Mitapivat appears to work best in patients with missense mutations, which are changes to a single building block in the PKLR gene that result in a slightly altered but still partially functional enzyme. Patients with other types of mutations, such as frameshift, deletion, or insertion mutations, may not respond as well or at all to treatment. One case report described a patient carrying two non-missense mutations who did not respond to mitapivat therapy.^[17]

Before starting treatment with mitapivat, doctors consider both the patient’s symptoms (phenotype) and their specific genetic mutations (genotype). Genetic testing of the PKLR gene is recommended to help predict whether a patient is likely to benefit from the drug. This personalized approach ensures that patients who are most likely to respond receive the treatment, while those who may not benefit can explore other options.^[17]

The clinical trials for mitapivat evaluated the drug’s safety and efficacy through several phases. Phase I trials focused on testing the drug’s safety in a small number of healthy volunteers and patients to determine the appropriate dose. Phase II trials involved more patients with pyruvate kinase deficiency to assess whether the drug effectively improved haemoglobin levels and other disease markers. Phase III trials compared mitapivat to placebo in larger patient populations to confirm its benefits and monitor for side effects over a longer period.

Mitapivat has been approved for use in adults with haemolytic anaemia due to pyruvate kinase deficiency. It represents a major advance in the treatment of this rare disease, offering the first targeted therapy that modifies the disease process rather than just managing symptoms. Patients in the United States and some other countries now have access to this medication, though availability may vary depending on local regulatory approvals.^[11]

Beyond mitapivat, researchers are exploring other innovative approaches to treating pyruvate kinase deficiency. Gene therapy is being investigated in preclinical studies, which are experiments conducted in laboratory settings and animal models before testing in humans. The goal of gene therapy is to introduce a healthy copy of the PKLR gene into a patient’s cells, allowing them to produce normal pyruvate kinase enzyme. Early results in animal models have shown promising efficacy and safety, raising hopes that gene therapy could one day offer a potential cure for pyruvate kinase deficiency.^[11]

Haematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, has been attempted in a few isolated cases. In this procedure, a patient’s blood-forming stem cells are replaced with healthy stem cells from a donor. The new stem cells produce red blood cells with normal pyruvate kinase enzyme. However, HSCT is not considered a standard treatment for pyruvate kinase deficiency because the procedure carries significant risks, including serious complications from the conditioning regimen (chemotherapy or radiation given before transplant) and the possibility of incomplete engraftment, where the donor cells do not fully take hold. The balance between potential benefits and serious risks must be carefully weighed for each patient.^[11]

Most Common Treatment Methods

• Blood transfusions
  • Administered to patients with severe anaemia or during aplastic crises to rapidly increase red blood cell counts
  • Decision based on symptom tolerance rather than a fixed haemoglobin threshold
  • Newborns with severe symptoms may require exchange transfusions to reduce bilirubin levels
  • More than half of children under five years require regular transfusions
• Phototherapy
  • Used in newborns to treat severe jaundice caused by bilirubin buildup
  • Special blue light helps break down bilirubin for elimination from the body
  • Approximately 93% of newborns with pyruvate kinase deficiency receive phototherapy
• Folic acid supplementation
  • Daily vitamin supplement to support increased red blood cell production
  • Prevents folic acid deficiency due to higher red blood cell turnover
  • Standard supportive care for all patients with pyruvate kinase deficiency
• Iron chelation therapy
  • Medications that bind to excess iron and help the body eliminate it
  • Used in patients who develop iron overload from repeated blood transfusions
  • Prevents damage to the heart, liver, and other organs
• Splenectomy
  • Surgical removal of the spleen to reduce red blood cell destruction
  • Performed in about 59% of patients, particularly those needing frequent transfusions
  • Results in median haemoglobin increase of 1.6 g/dL and reduced transfusion needs in 90% of patients
  • Delayed until at least five years of age when possible to reduce infection risk
  • Requires lifelong vaccinations and infection prevention measures
• Cholecystectomy
  • Surgical removal of the gallbladder when gallstones develop
  • Often performed at the same time as splenectomy
  • About 48% of patients who had splenectomy alone later require gallbladder removal
• Mitapivat (Pyrukynd)
  • First FDA-approved disease-modifying drug for pyruvate kinase deficiency
  • Oral pyruvate kinase activator taken twice daily
  • Increases enzyme activity and ATP production in red blood cells
  • Improves haemoglobin levels and reduces or eliminates transfusion requirements
  • Most effective in patients with missense mutations
  • Approved for adults with haemolytic anaemia due to pyruvate kinase deficiency
• Gene therapy (investigational)
  • Preclinical research introducing healthy PKLR gene copies into patient cells
  • Aims to enable production of normal pyruvate kinase enzyme
  • Promising efficacy and safety in animal models
  • Not yet available for human patients
• Haematopoietic stem cell transplantation (investigational)
  • Replacement of patient’s blood-forming stem cells with healthy donor cells
  • Reported in isolated cases only
  • Not considered standard treatment due to significant risks and complications
  • Associated with extensive toxicity and possibility of incomplete engraftment